9 Rickets, Osteomalacia, Renal Osteodystrophy - Jbjs Part 2

Review Article
Rickets, Osteomalacia, and

Renal Osteodystrophy
PART 11*
BY HENRY J. MANKIN, M.D.t, BOSTON, MASSACHUSETTS
Etiological Classification and Diagnosis of Rickets and Osteomalacia
As already indicated, the syndromes of rickets (and osteomalacia) are pathogeneti-

cally related, in that all are characterized by a diminution in available calcium, phosphate,
or both, and the clinical manifestations are highly stereotyped regardless of specific cause.
Thus a whole series of nutritional, absorptive, chemical, genetic, and toxic diseases result
in the general syndrome complex just described. The classic form of the disease, which
served as the model for Glisson’s description 141 and on which most of the early studies
were performed, is rickets caused by a dietary deficiency of vitamin D. The clinical,
roentgenographic, and laboratory data described in Part I of this review (The Journal of
Bone and Joint Surgery, 56-A: 101-128, January 1974) for the most part apply to this
form of the disorder. Because of generally improved nutrition and medical awareness,
classic vitamin D-deficient rickets or osteomalacia is rare in the industrialized Western
countries, and most of the recently reported series are in deprived population groups or
developing nations 57,71,73,103,125.169,212,262.309 Rickets caused by genetic errors, as typified
by vitamin D-resistant rickets, is more prevalent, particularly in communities where kin-
dreds which carry the trait are prone to intermarry Recently certain disease states and
toxic reactions to drugs have been implicated in the genesis of the syndrome, and with
better care for patients with chronic renal disease the rickets and osteomalacia of renal
osteodystrophy have become significant and particularly trying problems in management.
An etiological classification of rickets and osteomalacia is shown in Table I. The
following brief discussion of each of these categories emphasizes the methods of distin-
guishing them from one another.
Deficiency States
Inadequate intake of calcium or phosphorus, or insufficient vitamin D in the diet, in

time leads to classic deficiency rickets or osteomalacia. Fortunately these diseases are now
rare, at least in the United States. Vitamin-D supplements are added to many foods, and
informed parents can prevent calcium deficiency in their children, even those who are
unable to drink milk 127.133.163.262,338.340 In adults, chronic deficiency in calcium intake has
been implicated as a cause of postmenopausal osteoporosis rather than osteomalacia, but
so-called hunger osteopathy, a form of deficiency osteomalacia, is still seen among the
very poor and in emotionally disturbed or aged individuals on bizarre diets 54.187.245#{149} A
dietary deficiency of phosphate is very rare, since most foods contain this element in
reasonable quantity and it is difficult to eat any type of food without ingesting one to two
grams of inorganic phosphate per day 185,261
Reprinted in part from the Cyclopedia of Medicine, Surgery, Specialties. Philadelphia, F. A. Davis Co.,
1973. (Permission obtained from the author, editor, and publisher for reproduction of portions of the text and
illustrations.)
t Massachusetts General Hospital, Fruit Street, Boston, Massachusetts 02114.
352 THE JOURNAL OF BONE AND JOINT SURGERY

RICKETS, OSTEOMALACIA, AND RENAL OSTEODYSTROPHY 353
TABLE I
ETIOLOGICAL CLASSIFICATION OF RICKETS AND OSTEOMALACIA
I. Deficiency Rickets and Osteomalacia

A. Vitamin-D deficiency
B. Calcium deficiency
C. Phosphorus deficiency
D. Chelators in diet
II. Absorptive Rickets and Osteomalacia
A. Gastric abnormalities
B. Biliary disease
C. Enteric absorptive defects
III. Renal Tubular Rickets and Osteomalacia
A. Proximal tubular lesions
B. Proximal and distal tubular lesions
C. Distal tubular lesions (renal tubular acidosis)
1. Primary
2. Secondary
IV. Renal Osteodystrophy
V. Unusual Forms of Rickets and Osteomalacia
A. Rickets with fibrous dysplasia
B. Rickets with neurofibromatosis
C. Rickets associated with soft-tissue and bone neoplasms
D. Rickets due to anticonvulsant medication
E. Hypophosphatasia
When certain substances known to bind or chelate calcium are included in the diet in
large quantity, they may decrease the ionized calcium available for absorption
significantly 13.127,344 These materials include phytate (from certain
cereals) 40,240,245,344,374 oxalate (from spinach), phosphate (which produces an insoluble
salt when the ratio ofcalcium to phosphate exceeds one to two) Ii, and fatty acids (which
form an insoluble soap with
calcium) 16,127#{149}Phosphate may be similarly bound by an ex-
cess of calcium in the diet 11,127 or by the administration of aluminum salts which form
insoluble phosphate compounds Beryllium,
127#{149} when taken orally, is toxic and produces
severe rickets 244,333.342, a fact only partly explainable on the basis of the affinity of the
metal for phosphate. A similar lesion can be produced experimentally by magnesium 127#{149}
Absorptive Defects
Three types of absorptive defects may cause rickets and osteomalacia: gastric,
biliary, and enteric.
Gastric
In recent years, a number of reports have suggested a moderately high incidence of
osteomalacic bone diseases in association with partial gastrectomy and
gastroenterostomy 61 .84,85,105,150.165.187.246,292 . This disease , which appears to occur most
frequently in women and after the Polya or Billroth II procedure 61,165.246, rarely produces
severe osteomalacia 61.84,85,165.246 Morgan 245 reported that the interval between surgery
and onset of symptoms is approximately ten years. The exact cause ofthis syndrome is not
known, but it has been suggested that loss of the reservoir function of the stomach, poor
mixing of nutrients in the long proximal loop, rapid intestinal transport (dumping syn-
drome), occult biliary or pancreatic lesions, or possibly a deficiency in gastric lipolytic
factor, are responsible 105.161.245.327,372.386#{149} In any event, the disorder is usually accom-
panied by diarrhea, steatorrhea, and anemia 13,105 The diagnosis is sometimes difficult,
since the osteomalacia is relatively mild and elevation of the alkaline phosphatase can
sometimes be caused by concurrent biliary or pancreatic disease 105.245,386, The roent-
genographic finding of Looser’s lines is helpful, but a bone biopsy may be necessary to
establish the diagnosis 245,246
VOL. 56-A, NO. 2, MARCH 1974

354 H. J. MANKIN
Biliarv
Patients with significant biliary, hepatic, or pancreatic disease may have os-
teomalacia, and children with congenital biliary atresia may have florid
rickets 14.166.262,366 The pathogenesis of these disorders is complex, probably involving
both inability of the damaged liver to synthesize the polar metabolites of vitamin D 18 and
abnormal handling of fats in the intestinal tract. Vitamin D is fat soluble, and is selec-
lively swept through the enteric tract without absorption if the bile salts which are neces-
sary for proper emulsification and absorption of ingested fat are reduced in
amount 17.264.364 Dietary calcium may also become complexed to fatty acids to form in-
soluble calcium soaps, thus decreasing the amount of calcium available for absorption 17#{149}
The rapid movement of intestinal contents associated with steatorrhea may limit absorp-
tion by diminishing the time available for absorption of calcium and phosphate by the
intestinal villi 14,264
Enteric
The most severe forms of gastrointestinal rickets and osteomalacia occur in the syn-
dromes associated with malabsorption of nutrients from the small bowel 241,245.259.264.277#{149}
These include gluten-sensitive enteropathy 136,237,255,260 sprue celiac disease 241,
scleroderma, amyloidosis, regional enteritis, and tuberculous enteritis 245,264.386#{149} In addi-

tion, many mechanical derangements and surgical procedures which shorten the small
bowel may result in more or less severe rickets or osteomalacia The
64#{149} pathogenesis of
these disorders is probably directly related to decreased efficiency or decreased available
surface area of the small bowel, resulting in diminished intestinal absorption of calcium,
phosphorus, or vitamin D 17.245,364,386 The diarrhea and steatorrhea often associated with
these problems enhance the metabolic defect by increasing the rate of transport through
the intestine or by introducing fatty acids which may complex calcium or cause the se-
questration of vitamin D 17,364
Rickets and Osteomalacia Due to Renal Tubular Abnormalities

The discovery and synthesis of vitamin D and the elucidation of the role of sunlight
in the activation of the vitamin-D precursors changed the syndromes of rickets and os-
teomalacia from a therapeutic enigma to a socio-economic and public-health
problem 57.125,169.212.219 In the 1930’s, sporadic cases of rickets were recognized which
did not respond to treatment with the usual doses of vitamin D, and astute observations by
Albright and co-workers in 1937 separated a subcategory from the group of rachitic dis-
eases, which they called rickets resistant to vitamin D. Over the past three decades, as the
vitamin D-deficient states have become increasingly uncommon except in areas of ex-
treme poverty or under circumstances of extraordinary dietary restriction, the originally
rare syndromes defined by Albright and his co-workers have become the commonest
forms of rickets and osteomalacia seen in clinical practice in the United States. In addi-
tion, as the result of increasing understanding of renal physiology and the careful investi-
gations by Albright and associates 2.4, Lightwood and associates 214.215, Butler and
co-workers Fanconi 116, De Toni 98.99, Dent 91, Burnett and associates 42, Lowe and
co-workers 221 Winters and associates and others, a spectrum of renal tubular abnor-
malities have been identified which cause clinical rickets or osteomalacia and which in
many cases are insensitive to even large doses of vitamin D.
There are three general pathophysiological mechanisms involved in these disorders:
one, an increase in the clearance of phosphate by the proximal tubule resulting from de-
creased reabsorption; second, a failure in the production of hydrogen ion and its substitu-
tion for fixed base in the distal tubule; and third, a failure in the conversion of 25-hydroxy
vitamin D to 1 ,25-dihydroxy vitamin D, as a result of an abnormality presumably in the
THE JOURNAL OF BONE AND JOINT SURGERY

enzyme systems in the renal tubule. These mechanisms produce a hypophosphatemic

rachitic or osteomalacic syndrome which does not respond to treatment with the usual
doses of vitamin D. A number of workers in the field have suggested classifications for the
vitamin D-resistant rachitic and osteomalacic states 91.93,133,245.272.340 but it seems sim-
plest and most logical to divide them into three broad categories: (1) proximal tubular
lesions causing hypophosphatemic rickets; (2) distal tubular lesions resulting in acidosis;
and (3) combined lesions of both the proximal and distal tubules which cause the Fanconi
group of rickets and osteomalacia. A classification based on these categories is shown in
Tables II and III. The synonyms and eponyms are listed, and the renal tubular defects are
identified.
Proximal Tubular Rachitic and Osteomalacic Syndromes
In the proximal tubule of the kidney, inorganic phosphate, glucose, and amino acids
are reabsorbed. Numerous congenital (and some acquired) syndromes have been de-
scribed in which there is a failure in one or more of these functions, producing a rachitic
lesion of greater or lesser severity depending on the degree of resorptive defect and the
material lost 245.272.371
The pathogenesis of rickets in the hypophosphatemic syndromes is still unknown,
but two basic theories have been proposed, each supported by some experimental evi-
dence.
The first theory, advanced by Albright and associates and subsequently by Dent and
Harris is that the rachitic lesion results primarily from the renal tubular defect. Ac-
cording to this theory, a tubular phosphate leak, which is a primary genetic error, results
in hyperphosphaturia and hypophosphatemia 13.127.272#{149} Rickets and osteomalacia develop
because of phosphate deficiency at the sites of mineralization in the bones and the zone of
provisional calcification of epiphyseal cartilage. The resistance to vitamin D is thought to
result from the fact that in this disease the sterol has minimum effect on the rate of renal
tubular resorption of phosphate, while its important action on the sensitive gut cell re-
mains intact 8688.175.322 Thus, rickets and osteomalacia develop in the presence of a nor-
mal intake and absorption of calcium from the gastrointestinal tract 69, and high doses of
the vitamin (at levels which would cause hypervitaminosis-D in normal individuals) are
required to reverse the process even partially. Cited as evidence for this theory are: the
frequent extension of the leak to include glucose and amino acids as well as
phosphate 13.127,133; the rapid development of rickets in animals which are given a diet
which contains normal amounts of calcium and vitamin D but is deficient in
phosphate 220.331.332; the failure of calcium infusions to correct the phosphate leak in pa-
tients with the syndromes 119.204.263.272; the demonstration of anatomical and electron mi-
croscopic abnormalities in the tubules of individuals with certain of the genetic renal tubu-
lax syndromes 63.80.182; and the recent demonstration that in patients with renal tubular
hypophosphatemia, phosphate transport is and lacks a parathyroid hormone-
sensitive component 142
The second theory suggests that the primary lesion is a generalized ‘resistance’ to ‘ ‘
vitamin D 15.18.373 According to this concept, vitamin D, when present in physio-

logical amounts, is either not converted to its active polar metabolites in the liver or
kidney, or is ineffective because of end-organ insensitivity, possibly on the basis of a de-
fect in the enzyme systems in the gut and bone cells 19.89#{149} According to this view, the
primary lesion is a hypocalcemia, resulting from decreased absorption of calcium in the
gut 258.267#{149} This hypocalcemia leads to a profound secondary hyperparathyroidism, which
in turn produces further loss of bone mineral and a marked increase in phosphate clearance
by the kidney. The experimental evidence for this view includes: the finding of decreased
absorption of calcium from the enteric tract in patients with the lesion 355; the frequent
occurrence of hyperplasia of the parathyroid glands 2.115.153; the demonstration of an ab-
VOL. 56-A, NO.2, MARCH 1974

356 H. J. MANKIN
TABLE II
TYPES OF RICKETS AND OSTEOMALACIA ASSOCIATED WITH PROXiMAL AND PROXIMAL
AND DISTAL RENAL TUBULAR SYNDROMES
Renal R eabsorp tive Defect
H
Deficit
or
Amino Bicarb.
Disease P04 Glucose Acids H20 Base Protein Wastage Remarks
Proximal tubular syndromes

1. Vitamin D-resistant rickets + Sex-linked domi-
(VDRR, hypo- nant trans-
phosphatemic rickets, mission ; occas.
phosphate diabetes) autosomal domi-
nant, recessive or
sporadic
2. Vitamin D-resistant rickets + +
with glycosuria
3. Proximal Fanconi syn- + + + Recessive trans-
drome (VDRR with mission
glycosuria and
aminoaciduria)
4. Late-onset vitamin D- + Normal until
resistant rickets adolescence or
adulthood;
disease probably
not genetic
Proximal and distal tubular
syndromes
1. Proximal and distal + + + + + + + Autosomal reces-
Fanconi syndrome sive transmission
(Debr#{233}-DeToni-Fanconi
syndrome)
2. Lignac-Fanconi syndrome + + + + + + + Recessive trans-
(cystinosis, cystine mission; cystine
storage disease) crystals deposited
in many body
tissues
3. Oculo-cerebral-renal syn- + ± + + + Almost always in
drome (Lowe’s syndrome) males; assoc.
w. mental re-
tardation,
hypotonia, hy-
poreflexia,
cataracts,
glaucoma, and
acidosis
4. Superglycine syndrome + + + Hyperglycinuria;
(VDRR with hyper- marked muscle
glycinuria, hypophospha- weakness
temic rickets with
hyperglycinuria)
normality of vitamin-D metabolism in patients with the syndrome 17; and the recent sug-
gestion that some patients with classic vitamin D-resistant rickets respond to relatively
small doses of25-hydroxy vitamin D 270,302,
Clearly the pathogenesis of vitamin D-resistant rickets is still an enigma, but it now
seems probable that in some kindreds defective phosphate reabsorption causes the disor-
der, while in others a primary abnormality of vitamin-D metabolism is at fault.
Regardless of the specific pathogenesis, the primary metabolic abnormality observed
in these patients is a markedly reduced reabsorption of phosphate from the glomerular
filtrate in the proximal tubule, leading to excessive excretion of that metabolite in the
urine and a deficit in the plasma 42,91.127.129.157.233.245.272.365.373#{149}
TABLE III
CAUSES OF RENAL TUBULAR Acmosis
(H+ GRADIENT FAILURE OR BICARBONATE WASTAGE)
I. Primary Causes
A. Genetic renal tubular acidosis (Butler-Albright Syndrome)
1 . Infantile, self-limited type (autosomal recessive)
2. Delayed-onset, persistent type (autosomal dominant)
B. Diseases with multiple tubular abnormalities
1. Proximal and distal tubular Fanconi syndrome
2. Lignac-Fanconi syndrome
3. Oculo-cerebral-renal syndrome
4. Superglycine syndrome
II. Secondary or Acquired Causes
A. Diseases associated with altered globulins
1. Altered 7-S globulin states
2. Cryoglobulinemia
3. Macroglobulinemia
4. Lupoid hepatitis
5. Rheumatoid arthritis
6. Myeloma
7. Sj#{246}gren’ssyndrome
8. Hepatic cirrhosis
9. Amyloidosis
B. Diseases associated with abnormalities of carbohydrate metabolism
1 . Galactosemia
2. Hereditary fructose intolerance
C. Diseases associated with abnormalities in metal metabolism
1. Wilson’s disease
2. Mercury and other heavy metal poisoning
3. Cadmium toxicity (“ouch-ouch disease”)
D. Endocrinopathic states
1. Hyperthyroidism
2. Hyperparathyroidism (primary and secondary)
3. Vitamin D-deficient rickets and osteomalacia
4. Hypercalcemia
E. Pyelonephritis
F. Drug toxicity
1. Outdated tetracycline
2. Phenacetin
3. Paraldehyde
4. Amphotericin B
5. 6-Mercaptopurine
6. Sulfanilamide
Four types of rickets associated with lesions of the proximal tubule have been re-
ported to date:
1 . The simplest type is the classic (and commonest) form of renal tubular rickets -
vitamin D-resistant rickets, otherwise known as hypophosphatemic rickets or phosphate

diabetes 91.93,133,157,245,272,361 In most patients with this disease there is a positive family
history Excellent
23i studies 42.356.379 have established that the primary mode of transmis-
sion of the syndrome is a sex-linked dominant and that the abnormal gene is carried on the
long arm of the X chromosome 272 Affected females transmit the defect to about half of
their sons and daughters, and affected males transmit it to all of their daughters and none
of their sons 272 Occasionally the disorder arises sporadically or is transmitted as an au-
tosomal dominant 42.356 The disease may be recognized when a child is as young as three
months old or, in its milder forms, may not be noticed until the age of two or older.
Hypophosphatemia and reduced phosphate reabsorption by the kidney may be present in
the non-rachitic kindred of the proband, and may be the only detectable manifestation in
some generations Unlike patients with vitamin D-deficient rickets, children with the
vitamin D-resistant disease rarely have systemic manifestations, and have little hypotonia,
apathy, irritability, or muscular weakness The overt
133.245.272 manifestations of the dis-
ease are confined to the skeletal system.
358 H. J. MANKIN
Most ofthe children with resistant rickets are normal in length at birth, but by the age
of two, even when treated, they usually fall below the third percentile in
height 79.157.272.336,356 Many show genu varum, or less commonly, genu valgum, enlarged
wrists and ankles, a rachitic rosary, and frontal bossing. Abnormalities of the spinal col-
umn and pelvis are usually absent. Although some reports have suggested that normal
height may be achieved with proper treatment 314316, most children with the syndrome are
dwarfed 160.231.280.318.336,353 Craniosynostosis, uncommon in vitamin D-deficient rickets,
seems to occur frequently in the resistant form 68.93,179.272#{149}
Roentgenographic studies demonstrate typical alterations in the epiphyseal lines, in-

distinguishable in early life from those of vitamin D-deficient rickets. As the child ages
and has periods of adequate treatment (or occasional episodes of hypervitaminosis-D), the
metaphyseal areas may show transverse sclerotic lines at irregular intervals. In adults with
this syndrome, roentgenograms show typical thinned cortices and irregular fuzzy
trabeculae in the long and flat bones, but Looser’s lines are less commonly seen in this
disease than in deficiency osteomalacia 70.210.272,354
Laboratory studies usually show a normal serum calcium, and invariably show a
markedly depressed serum inorganic phosphate, the latter often falling below 2 milligrams
per 100 milliliters, even in young children 79.129.272.356.361.365#{149} The alkaline phosphatase is
often elevated. Urinary calcium excretion is usually low 245.272.355, while the twenty-
four-hour urinary phosphate excretion is often normal or slightly low 272,355 and the fecal
excretion of calcium is high 69,355#{149} Urinary reabsorption of phosphate is low, with the per-
centage of tubular reabsorption of phosphate ranging between 40 and 70 per
cent 157.245,373,379
Perhaps the most striking feature of the syndrome is the failure of the patient to re-
spond to large and sometimes massive doses of vitamin D 133.157#{149} With doses of vitamin D
ranging from 150,000 to 1 ,200,000 units daily, the serum inorganic phosphate may rise to
4 to 5 milligrams per 100 milliliters, while the alkaline phosphatase falls to normal. Un-
fortunately, such treatment, if sustained, may result in hypercalcemia, nephrocalcinosis,
and metastatic calcification in the soft tissues 129.157,160,280,361 The hypercalcemic toxic
state may occur with extraordinary rapidity, and patients on such a routine must be care-
fully observed at regular intervals for evidence of toxicity.
2. The second type of proximal tubular lesion is vitamin D-resistant rickets with
glycosuria, which is much less common than classic vitamin D-resistant rickets and prob-
ably is a variant of it 91.93.I33.157,245.272.279.371#{149} In this syndrome, the patients have an ab-
normal resorptive mechanism for both inorganic phosphate and glucose, leading to
hypophosphatemic rickets and mild to moderate glycosuria, without diabetes or evidence
of pancreatic disease. Little is known of the genetic transmission of this disorder, but the
clinical manifestations and response to vitamin D are essentially the same as those of vi-
tamin D-resistant rickets.
3. The third type in this group is theproximal Fanconi syndrome, in which, early in
life, the patient is noted to have defective reabsorption of phosphate, glucose, and many
amino acids 91,93,116.133.157.279,371 In this syndrome, the pathogenesis and clinical manifes-
tations are the same as in the other two types, but the disease is often more florid, with
early development of severe rachitic lesions and pathological fractures 133 Despite the
presence ofabnormal amounts ofamino acids in the urine, the serum levels ofamino acids
are usually normal #{176}. Occasionally as patients with the proximal Fanconi syndrome grow
older they develop chronic liver disease, suggesting the possibility that the aminoaciduria
may reflect or cause a widespread metabolic abnormality 13,133#{149} The principal amino acids
in the urine of these patients are threonine, serine, glycine, alanine, histidine, and
arginine 90
Fraser and Salter 133 suggested that it is important to distinguish this type of resistant
rickets from the other two, since in their experience the prognosis for the proximal Fan-

coni syndrome is better, particularly if the patient receives early treatment with adequate
(high) doses of vitamin D. Although the epiphyseal and osseous changes visible on the
roentgenograms are severe with this syndrome, it appears to be much less refractory to
vitamin D than the other two, and the bone changes, chemical abnormalities, and
aminoaciduria respond reasonably well to chronic administration of large doses of the vi-
tamin.
4. A fourth and rare type of hypophosphatemic syndrome, which is refractory to vi-
tamin D and does not become manifest until late adolescence or early adulthood, has also
been described 36,95,183.224.300,376 Patients with this very unusual disorder are normal in
childhood, but fairly marked osteomalacic changes develop in early adulthood. There is
no evidence for a genetic error in these patients, and it has been suggested that the de-
creased tubular reabsorption reflects some acquired lesion, possibly on a toxic
basis 95.183.376 In the patient reported by Riggs and co-workers parathyroidectomy
#{176}#{176},
produced a striking remission in the disease, and subsequent administration of parathor-

mone reproduced the chemical lesion. On this basis, these authors proposed the theory
that in this lesion in adults action of parathyroid hormone on the tubules is the cause of the
phosphate leak, rather than a primary tubular defect 3O0
Proximal and Distal Renal Tubular Rachitic and Osteomalacic Syndromes

In this group of rare disorders, rickets and osteomalacia are associated with multiple
abnormalities in the function of the proximal and distal tubules and frequently with very
severe derangements of acid-base and water metabolism 208 The additional tubular
deficits in these syndromes include impaired reabsorption of water, fixed base, protein,
and bicarbonate 34,208,272,283 Diminished resorption of these metabolites results in
acidosis, dehydration, and hyperproteinemia, and may lead to rapid death due to uncon-
trollable metabolic imbalance 34.208.383 Four syndromes have been identified in this group:
the proximal and distal Fanconi syndrome, the Lignac-Fanconi syndrome, the oculo-
cerebral-renal syndrome, and the superglycine syndrome.
1 . The proximal and distal Fanconi syndrome (the Debr#{233}-De Toni-Fanconi syn-
drome) is a genetic error of renal tubular function believed to be associated with an
anatomical deformity of the renal tubule. By microdissection studies of the kidney of pa-
tients with this syndrome, Darmady and Stranack 80 and Clay and associates 63 demon-
strated a so-called swan-neck deformity in the renal tubule. In addition, study ofthe tubu-
lar microstructure by light and electron microscopy has shown abnormalities in the cells of
both the proximal and the distal tubules The
182#{149} disease is transmitted as an autosomal
recessive and is probably genetically unrelated to either the proximal Fanconi syndrome
already described or the Lignac-Fanconi syndrome 208, in which the tubular lesions are
similar but crystals ofcystine are deposited in soft tissues throughout the body.
Patients with the proximal and distal Fanconi syndrome have all the defects of the
proximal tubule seen in the proximal Fanconi syndrome. They usually have very severe
hypophosphatemic rickets 34.99,186,229.272 with epiphyseal plates measuring up to several
centimeters in height and cortices so thin that multiple fractures occur within the first few
months of life 133.186 Roentgenograms may show that the osseous structures have a dif-
fuse ground-glass appearance, indicating the marked deficiency of mineral in the
skeleton 46.186
In addition to the hypophosphatemic diathesis, however, these patients have other

tubular reabsorptive defects which affect water, protein, fixed base, and bicarbonate
metabolism. Clinically, there is a metabolic aberration characterized by dehydration,
hyperchloremia, hyponatremia, hypokalemia, and acidosis with an alkaline
urine 34.173.208,229.272
The diagnosis is made readily by chemical analysis of the serum and
urine 13,127.133.173.208 Serum calcium is usually low; serum phosphate, markedly reduced;

360 H. J. MANKIN
and alkaline phosphatase, elevated. Serum amino acids are generally normal, while elec-
trolyte and pH studies show an acidosis associated with a decrease in serum sodium and
potassium and an increase in chlorides. Urinalysis usually demonstrates a low specific
gravity, an alkaline pH, glycosuria, and many amino acids in increased
quantities 99.173.208
Patients with proximal and distal Fanconi rickets are usually quite ill. Survival during
early life is dependent on the severity of the defect. The phosphate reabsorptive deficit in
this disease is usually less refractory to vitamin D than that in vitamin D-resistant rickets.
Doses of 25,000 units daily may produce remarkable healing of the rachitic
abnormalities Administration of phosphate 245 and of an alkalinizing solution to treat
the acidosis frequently is successful in suppressing many of the manifestations of the
disease 173,245.272
Occasionally an adult patient is encountered who has all the findings ofthe proximal
and distal tubular Fanconi syndromes 334.368 Although some of these patients may have a
genetic abnormality, with delayed onset of symptoms related to the mildness of their dis-
ease, most ofthem appear to have an acquired abnormality often associated with a chronic
disease, most frequently multiple myeloma 72,83,111,329 or a toxic reaction to heavy metal
poisoning Adult patients with the disorder may have severe, crippling bone disease
with rapidly progressive osteomalacia
2. The Lignac-Fanconi vndrome (cystinosis, cystine storage disease) is essentially
the same as the proximal and distal tubular Fanconi syndrome except that crystals of
cystine, a sulphur-containing amino acid, are deposited throughout the soft
tissues 127,133,186,208.272.383 This disease must be distinguished from another genetic
metabolic disorder, cystinuria, in which the patient excretes cystine, lysine, arginine, and
ornithine in large quantities in the urine and has widespread systemic abnormalities, but
does not have the signs and chemical findings ofrickets 279.371W
The Lignac-Fanconi syndrome is now fairly clearly identified as a genetic disease

which appears to be transmitted as an autosomal recessive 21.33.208.312#{149} The metabolic aber-
ration is complex, but it is clear that in addition to the abnormalities of renal tubular func-
tion resulting in loss of phosphate, glucose, amino acids, water, base, bicarbonate, and
sometimes protein, there is a widespread abnormality of the metabolism of
cystine 21.33.208,218 Worthen and Good 383, and subsequently Patrick 278, suggested that
there may be deficient synthesis of sulfhydryl enzymes and perhaps a specific deficit of
cystine reductase. Pathologically, doubly refractile cystine crystals are found in the con-
junctiva, cornea, liver, spleen, lymph nodes, renal parenchyma, and bone
marrow 21.33.127,133,200,218,312,383 Some controversy exists as to whether these crystals pro-
yoke an inflammatory response 21.182.218.383#{149} Proponents of the inflammatory response
theory hold that the gradual development of hepatic fibrosis and glomerulonephritis is the
result of scarring around the deposited crystals. The other theory is that the crystals are
innocent in causation of the syndrome, and merely reflect one part of a multiple-enzyme
abnormality which results in the renal tubular, hepatic, and glomerular changes.
Patients with this disorder usually appear normal at birth but by the age of two years
and, in florid cases, as early as three to four months, they show evidence of diffuse
illness 32,76.200.208 Afflicted children become irritable, apathetic, and anorectic, lose
weight, and fail to thrive. If the nephrogenic diabetes insipidus is severe, they become
dehydrated and acidotic. Rickets supervenes soon after the onset of the disease and is
often quite severe. There may be periodic episodes of hypokalemia, with profound ab-
normalities of muscle, nerve, and occasionally cardiac function 208#{149}
Slit-lamp examination may reveal cystine crystals in the cornea and conjunctiva, the
liver may be slightly to moderately enlarged and changes consistent with rickets are
found in the lower extremities. As in other forms of rickets, there are no distinguishing
characteristics which separate this form from the others.

The diagnosis of Lignac-Fanconi syndrome can be made on the basis of the serum
and urine findings, although it should be noted that these findings may be identical to
those seen in several other types of proximal and distal tubular rickets 133,208 The serum
calcium is usually low normal; the serum inorganic phosphate, uniformly low; and the
alkaline phosphatase, usually elevated. Determination of serum electrolytes as a rule
demonstrates hypokalemia, hyponatremia, hyperchloremia, and acidosis, the degree of
these changes depending on the severity of the disease. Analysis of the urine of a patient
with florid disease shows an alkaline pH, low specific gravity, proteinuria, and
glucosuria. Quantitative excretory studies show hypocalciuria, diminished percentage of
tubular reabsorption of phosphate, increased excretion of fixed base and bicarbonate, and
aminoaciduria 127,208 The amounts of amino acid in the urine vary from patient to patient
and in any one patient from day to day, but usually exceed 200 milligrams in twenty-four
hours 208 The amino acids most often found are lysine, serine, aspartic acid, threonine,
valine, leucine, phenylalanine, tyrosine, proline, and cystine 127.208#{149} Proteinuria in the
Lignac-Fanconi syndrome may also be somewhat unusual in that relatively large amounts
ofalpha 2, beta, and gamma globulins 44.102 may be found. This finding distinguishes this
syndrome from most of the other renal lesions in which albumin or other proteins of low
molecular weight are excreted.
The finding which distinguishes this lesion from the others is the presence of cystine
crystals in the bone marrow peripheral leukocytes 200 or lymph nodes 127#{149} These
crystals may be readily seen in fresh unstained microscopic preparations of the buffy coat
of a blood sample or aspirated bone marrow 133.200 The crystals are doubly refractile in
polarized light and have a characteristic roentgenographic diffraction pattern 135#{149} The
material is soluble in water and usually is not seen in fixed stained specimens of tissues.
The error in cystine metabolism in this disorder has not been established, but it should be
noted that plasma levels are normal and that attempts at inhibition of cystine metabolism
by dietary restriction and penicillamine administration have failed to alter the course of the
disease 76
Patients with the Lignac-Fanconi syndrome are often seriously ill, even early in the
course ofthe disorder. Death may result from hypokalemic crisis, chronic dehydration, or
intercurrent infection. The rachitic manifestations, although usually severe, may be
modified considerably as the general state ofthe patient deteriorates, the so-called paradox
of rickets already described. If the patient survives the crucial early phases of the disease
and receives adequate therapy with alkalinizing solutions, neutral phosphate, vitamin D
(in low or moderate doses), and water replacement, the rickets clears and the acidosis
becomes less marked 208.272.274 With advancing age, however, hepatic fibrosis and
glomerulonephritis develop and imperil the child’s life. It is rare that patients with florid
cystine storage disease survive beyond the age often years despite adequate treatment.
Cystinosis in adults, a rare disorder of unknown etiology differs
213, from Lignac-
Fanconi disease in that osteomalacia usually does not occur and the disease is benign. The
deposits ofcystine crystals in various organs, however, are identical to those seen in chil-
dren with the Lignac-Fanconi syndrome.
With three entities whose eponyms include the name of Guido Fanconi, there are
obvious problems related to nomenclature. All three diseases at one time or another are
referred to as the Fanconi syndrome. To make matters worse, there are at least eight other
diseases not associated with rickets that were described to some extent by this prolific
investigator and bear his name Historically, much ofthe confusion arose from the fact
that cases ofthese three disorders were reported by several authors, but subsequently were
found to be examples of disorders other than those originally suggested. Thus De Toni 98
in 1933 reported on a case ofwhat was to be called proximal and distal Fanconi syndrome,
and Debr#{233}
and associates 81 described a similar case in 1934. Then, in 1936, Fanconi 116
described three cases of what appeared to him to be a variant of this newly described en-
VOL. 56-A, NO. 2, MARCH 1974

362 H. J. MANKIN
tity. In these cases, the predominant functional derangement was in the proximal tubule.
Subsequently Fanconi’s name was used in the eponym of this proximal defect (proximal
Fanconi syndrome) and was also added to the names of Debr#{233} and De Toni in the eponym
of the group characterized by a more widespread disorder of tubular function Later one
of Fanconi’s three patients died and autopsy revealed cystine crystals in the soft tissues
and bone marrow. Search of the literature for cystine storage syndromes then uncovered a
report of two cases by Lignac 216 published in the mid-1920’s. Lignac’s name was there-
fore added to the eponym ofthe third form ofthe disease (Lignac-Fanconi syndrome).
The classification shown in Table II lists the various eponyms used. Perhaps, as has
been done in this table, it would be best to retain the name Fanconi in all three syndromes,
but to identify the site of the lesion in each instance: proximal Fanconi syndrome, denot-
ing abnormalities in the proximal tubules; proximal and distal Fanconi syndrome
(Debr#{233}-De Toni-Fanconi syndrome), indicating abnormalities in both proximal and distal
tubules; and Lignac-Fanconi syndrome, denoting proximal and distal tubular abnor-
malities (as in the previous group) combined with deposition ofcystine crystals.
3. The oculo-cerebral-renal syndrome, first described by Lowe and co-workers 221
in 1952, is otherwise known by the eponym, Lowe’s syndrome. A known genetic disease,
it was originally thought to be transmitted as a sex-linked recessive, occurring only in
males 60.221.239.313 Recently it has been reported in females 307,358 and the presence of
lenticular opacities in the mothers of affected males indicates an X-linked partially domi-
nant transmission pattern 168W Although the principal clinical manifestations are those of
hypophosphatemic acidotic rickets, there are a number of anatomical and metabolic ab-
normalities which distinguish the oculo-cerebral-renal syndrome from other forms of
tubular dysfunction. Typical patients with this syndrome, in addition to rickets, have un-
descended testes 168 and a variety of abnormalities in the central nervous system and
eyes 60.168#{149} There is severe mental retardation and the child with this disease is inattentive
and hyperexcitable, emitting high-pitched screams. The limbs are hypotonic, either mov-
ing in a repetitive, purposeless manner or being held in bizarre postures. Motor power in
the extremities is poor, and the deep tendon reflexes are usually absent.
The eyes show changes consistent with megalocornea and bulphthalmos 60.221#{149} Con-
genital cataracts are present in almost all of these patients, and glaucoma is frequent even
in young children. Nystagmus is common, and the movements are described as searching
or random. The changes of moderately severe rickets, combined with the aforementioned
ocular and cerebral signs, frontal bossing, and cranial deformities, produce facies that are
characteristic ofthis disorder.
The findings in the blood and urine are those of a severe hypophosphatemic vitamin
D-resistant rickets. In addition, however, urinalysis commonly shows: proteinuria with the
excreted protein being a beta globulin 44; glycosuria in about half the patients; and red
cells, white cells, and granular casts. The urine is often alkaline despite the systemic
acidosis, and shows evidence of inadequate ammonia formation and increased bicarbonate
loss. Amino acids are excreted in excessive amounts, especially ornithine, lysine, cystine,
and arginine 60.313#{149}
The exact nature of the renal lesion in the oculo-cerebral-renal syndrome is un-
known. Since there is almost always a decrease in tubular reabsorption of phosphate, and
somewhat less constant decreases in the reabsorption of glucose and amino acids, the
proximal tubule is affected. The proteinuria and cylindruria also suggest a glomerular le-
sion and many of the patients show a progressive decline in renal function 380#{149} Involve-
ment of the distal tubule is suggested by the water depletion which occasionally occurs
and by the failure of hydrogen ion substitution for fixed base or bicarbonate wastage, or
both 168,239 Lack of hydrogen ion substitution and bicarbonate wastage, singly or in com-
bination, produce classic renal tubular acidosis which is superimposed on the hypophos-
phatemic state, increasing the severity of the rachitic disease 239

Although the oculo-cerebral-renal syndrome is listed with the vitamin D-resistant

syndromes, the rickets seen in this disorder is not refractory. Complete healing of the
rickets may be produced by doses of vitamin D as low as 2,500 units per day, when ac-
companied by the administration of alkalinizing solutions 133#{149}There is no known treat-
ment for the ocular or cerebral manifestations 221,313 Despite adequate treatment of the
metabolic disease, many children with this disorder die of chronic renal disease, dehydra-
tion, or intercurrent infection. Long-term survival has been reported, however, and in the
patients who do survive the metabolic abnormalities become less severe, the rachitic and
renal lesions tend to disappear, and no further therapy may be required 60#{149}
4. The superglycine syndrome, otherwise known as hypophosphatemic rickets with

hyperglycinuria, is a rare disorder of adolescents, first described by Dent and Harris in
1956 . Clinically the findings are those of late-onset hypophosphatemic rickets or os-
teomalacia, but, in sharp contrast to the findings in the vitamin D-resistant group, there is
rather profound muscle weakness and atrophy The patients
290,319#{149} with this disease are
usually normal until they are twelve to sixteen years old 190.319#{149}The disease then becomes
manifest and chemical studies disclose a decrease in tubular reabsorption of phosphate
and often glucose, as well as a mild degree of renal tubular acidosis, with chemical
changes consistent with bicarbonate wastage 164.190#{149}In addition, analysis ofthese patients’
urine for amino acids usually demonstrates extraordinarily high concentrations of glycine
and glycyl proline l64.190.319 Patients with this syndrome have responded to moderate
doses of vitamin D combined with alkalinization and phosphate supplements.
Rickets and Osteomalacia Associated with Renal Tubular Acidosis
Renal tubular acidosis is a clinical syndrome caused by disordered acidification of the

urine in the kidneys 108,248.251.295,321 The normal mechanism by which the kidneys deal
with an acid load includes reabsorption of filtered bicarbonate and excretion of acid 248#{149}
Both of these steps take place in the tubules where hydrogen ion is excreted by the tubular
cells and exchanged for sodium, which is reabsorbed 248, 251 When one or both of these
mechanisms fails, the resulting syndrome is characterized biochemically by a hyper-
chloremic, hyponatremic, and hypokalemic acidosis without azotemia; and by an map-
propriately high urinary pH, bicarbonaturia, and a reduced excretion of titratable acid or
ammonia 177.251.295 The exact nature ofthe renal lesion or lesions which produce the syn-
drome is not known, but there is compelling evidence to suggest that at least two (and
probably several) mechanisms exist 251#{149} In one ofthese, called by Morris 248,251 classic or
Type 1 renal tubular acidosis, failure of the tubular cells to excrete acid creates a steep
gradient between the hydrogen ion concentration of the urine and that of the peritubular
space 251,295.297.321.384 Although it is tempting to speculate that the basic abnormality in
this disorder is a deficiency of renal tubular carbonic anhydrase, studies have shown the
concentration ofthis enzyme to be normal 385#{149}
The second form of renal tubular acidosis, called Type 2 by Moms 251, appears to
result from bicarbonate wastage from the proximal or distal tubules. In this condition,
despite normal plasma bicarbonate levels, the tubular reabsorption of bicarbonate is re-
duced by at least 15 per cent 27,251.295 This is the disorder usually found in the Debr#{233}-De
Toni-Fanconi syndrome or Lowe’s syndrome, but it may also be present in vitamin
D-deficient rickets or in secondary hyperparathyroidism, suggesting that excessive secre-
tion of parathormone may materially reduce the reabsorption of bicarbonate 251.252.256,257#{149}
Regardless ofthe specific cause, the results are increased excretion ofsodium, potas-
sium, and bicarbonate, retention of chloride , and metabolic acidosis 22.177.215,251.296.317.321W
Frequently water reabsorption is also decreased, resulting in profound dehydration. The

mechanism causing the bone lesions in renal tubular acidosis is not as yet clearly defined.
Albright and co-workers 2,6 suggested that hypocalcemia resulted from the excessive ex-
cretion of calcium as fixed base, and that chronic hypocalcemia caused secondary hyper-

364 H. J. MANKIN
parathyroidism, phosphaturia, hypophosphatemia, and bone lesions. The effect of

parathormone on bicarbonate reabsorption 252.257 would further aggravate the acidosis and
tend to perpetuate the syndrome. This concept is difficult to apply to patients who are not
significantly hypocalcemic 285 and it has been suggested that the acidosis alone may be
sufficient to mobilize calcium from the skeleton and produce the bone lesions 146.167.209#{149}
The phosphaturia which is often present in patients with renal tubular acidosis may be a
manifestation of an intrinsic renal tubular lesion caused by the acidosis 158 or a concomi-
tant of the potassium deficiency 234#{149} Intestinal absorption of calcium is usually
decreased 146, possibly as a result of impairment of renal formation of 1 ,25-dihydroxy
vitamin D. Such a decrease would favor the development of a rachitic or osteomalacic
syndrome.
Over 70 per cent of the patients with chronic renal tubular acidosis have
nephrocalcinosis 22,70,177,245, This lesion may result from chronic hypercalciuria, but re-
cent studies have suggested that calcification of the renal parenchyma is in some way cou-
pled with the decrease in concentration of citrate found in the serum and urine of patients
with this disorder 253 It has been speculated that loss of the complexing action of citrate
on calcium ions favors precipitation ofcalcium in the renal tissues.
Of the metabolic problems associated with renal tubular acidosis, perhaps the most
dramatic and certainly the most threatening are the profound hypokalemic crises 268.295.321
During minor metabolic stress a patient with renal tubular acidosis may suddenly become
hypokalemic and have severe prostration, hypotonia, fever, and paralysis. Ifthe diagnosis
is overlooked, cardiac or respiratory collapse may occur and be fatal. Correction of the
acidosis and administration of potassium cause rapid improvement, with complete recov-
ery in a short period of time.
Renal tubular acidosis associated with skeletal disease was first described by Light-
wood in 1935 214 In the following year Butler and co-workers added several cases, and
in 1940 Albright made an extensive
6 study ofthe skeletal changes in one ofthese patients
and speculated on the metabolic abnormality. The condition, now known as the
(Lightwood-) Butler-Albright syndrome, is thought to be a primary genetic abnormality.
Recent studies by Huth and associates suggest that there are two forms: an infantile
form that is self-limited, and a late-onset form in which the disease persists throughout
life. The infantile form, which is rare and more prevalent in males, is believed to be a
recessive genetic error in which there is an abnormality in the transport enzyme systems
for hydrogen ion or bicarbonate, an error which either corrects itself spontaneously or is
so slight that the abnormality disappears with the alterations in metabolism which occur
with aging. The lesion is present at birth and may result in severe complications if
unrecognized 215#{149} With supportive therapy, generally consisting of alkalinization alone or
supplemented with vitamin D and potassium, the patients become clinically asymptomatic
and at about one year old are found to have normal renal function 10i,177#{149} Acidosis is no
longer present, the serum electrolytes are normal, and the pH of the urine responds ap-
propriately to an acid load.
In the delayed-onset type 177.293, the lesion is more clearly genetic and is believed to
be transmitted as an autosomal dominant with variable expressivity and penetrance. Girls
are more frequently affected than boys, and the disease usually is not manifest before a
child is one or two years old. The renal lesion in these patients persists and generally
treatment must be continued throughout life.
The clinical findings in these children are quite dramatic, as might be anticipated in
such a broad metabolic abnormality. The symptoms include failure to thrive, anorexia,
vomiting, dehydration, apathy, weakness, and polyuria 70.107.126,177,215#{149} Bone pain,
pathological fractures, and enlarged joints may indicate the presence of rickets, and ure-
teral colic may signal the presence of nephrocalcinosis. Minor metabolic stress, such as a
glucose tolerance test, may precipitate a hypokalemic crisis characterized by severe pros-

tration, fever, hypotonia or flaccid paralysis, respiratory distress, and cardiac arrhythmia.
The diagnosis of this disorder rests on careful evaluation of the laboratory data. The
combination of hyponatremia, hypokalemia, hyperchloremia, decreased plasma bicarbo-
nate, and low pH in the presence of an alkaline urine (pH of 6.0 or greater) is virtually
diagnostic 295.296.321 If the patient also has rickets or osteomalacia there may be normal or
low serum calcium levels, hypercalciuria, hypophosphatemia, and an elevated alkaline
phosphatase.
As previously noted, the Debr#{233}-De Toni-Fanconi, Lignac-Fanconi, Lowe’s, and
superglycine syndromes are all associated with some degree of renal tubular acidosis. The
defect in most of these conditions has been found to be the Type 2 abnormality 251, and
obviously represents an important cause ofsome ofthe metabolic aberrations displayed by
the affected patients 320
As indicated in Table III, there are many acquired forms of renal tubular acidosis
caused by bicarbonate
wastage, failure to produce a hydrogen ion gradient, or
both 177,248.251,295,296,320 Most of these lesions are associated with systemic disorders in
which there is an alteration of the serum globulins 67,189,238.249,250.325,326,360,377 a geneti-
cally transmitted disorder of intermediary carbohydrate metabolism 247.251,252, abnormal
concentrations of certain metals ‘ 10.120, 194,367 endocrinopathies ‘ 18,1 76.387,
pyelonephritis 207, or drug sensitivity or intoxication 94,109,230 Although the handling of

bases and phosphate in the kidney of many of these patIents is grossly disordered, rickets
or osteomalacia is less prominent in these conditions than in the Butler-Albright syndrome
or in the genetic forms of proximal and distal renal tubular rickets. The exception,
perhaps, is cadmium toxicity, which is otherwise known as “ouch-ouch disease” because
ofthe bone pain associated with the chronic osteomalacia caused by excessive ingestion of
this element 110,194,367
Renal Osteodystrophy
Chronic glomerular renal

disease, resulting in renal insufficiency, azotemia, and
acidosis, has a profound effect
on the skeletal system. The changes include rickets or Os-
teomalacia, osteitis fibrosa cystica, osteoporosis, osteosclerosis, and metastatic
calcification. The extraordinary clinical picture produced by this combination of patholog-
ical states was termed renal osteodystrophy by Liu and Chu in 1943 217 replacing a series
of less descriptive terms including renal nanism, renal dwarfism, renal infantilism, renal
rickets, and renal hyperparathyroidism.
The association of chronic renal disease and skeletal disorders was first described by
Lucas 222 in 1883, who reported on several adolescent males with albuminuria and rick-
ets. He believed that the process resulted from ‘bad habits’ ‘ ‘ (a delicate phrase for mastur-
bation), and claimed cures for four patients who “mended their ways.” By 1927, studies
by several investigators, including Barber 24, Cameron ‘, and Parsons 276, had clearly
established that children with chronic renal failure have delayed skeletal development,
fibrous lesions of the bones, dwarfism, enlarged joints, and the bowed extremities of rick-
ets. It soon became apparent that cod-liver oil, and later vitamin D, had little effect on
these skeletal abnormalities, and although the pathogenesis was obscure, the rickets as-
sociated with renal disease came to be considered a separate and distinct form ofthe rachi-
tic syndrome. In 1937, Albright and his co-workers first demonstrated skeletal lesions
consistent with hyperparathyroidism in patients with chronic renal failure, and shortly
thereafter the histological observations of Ginzler and Jaffe 140 and of Follis and
Jackson 123,124 confirmed the hypothesis that the bone changes included not only os-
teomalacia but also osteitis fibrosa cystica. Parsons 276 first noted osteosclerotic lesions in
patients with chronic renal disease, but failed to associate them with the osteodystrophic
state. However, in 1941 Ginzler and Jaffe 140 described the autopsy findings of marked
osteosclerosis of bone in a patient with chronic renal disease, and suggested a relationship

366 H. J. MANKIN
to renal osteodystrophy. These findings were later confirmed by Crawford and associates
in 1954
The pathogenesis of the bone changes in renal osteodystrophy is complex and has
been the subject of considerable study and speculation 65.I22,191.198.273,323.347350 The
chronic azotemia has a profound effect on the metabolism of vitamin D, calcium,
parathormone, and phosphate, and these metabolic alterations lead to the pathological
changes and clinical manifestations ofthe disease.
Vitamin-D metabolism in uremic patients has been extensively studied since Liu and
Chu first observed in 1943 2 1 7 that larger amounts of the vitamin were required for control
of the bone disease in patients with renal osteomalacia than in those with the deficiency
type. Dent and co-workers 96, and later Stanbury and Lumb confirmed the “in-
creased resistance to vitamin D’ ‘ in uremic patients. Recent studies by Lumb, Mawer, and
Stanbury 223 indicated that the “resistance’ ‘ is not related to failure of absorption of the
vitamin, since this process is not impaired even in severely ill patients. The studies of
Avioli and associates 20 indicated that the metabolism of the vitamin is abnormal and that
biologically inert metabolites accumulate. Although the exact nature of the intestinal ab-
normality in renal disease is still unknown, the current concept is that the reduction in
renal mass interferes with the conversion of 25-hydroxy vitamin D to 1 ,25-dihydroxy vi-
tamin D, thereby decreasing the absorption of calcium from the gut and favoring the de-
velopment of rickets and osteomalacia 8.39.132,273.339.382#{149}
Calcium metabolism has also been studied extensively in uremic

patients 65.191,196.198.348 Despite the fact that the renal tubule is often badly damaged in
end-stage renal disease, calcium wasting is rare and generally occurs only in the occa-
sional patient who has sodium-wasting nephritis 65.191 In most uremic patients renal ex-
cretion ofcalcium is markedly reduced, probably reflecting the decreased glomerular flow
and the contraction of the extracellular pool 191.198,234,273.349 Urinary calcium excretion is
generally less than sixty milligrams per twenty-four hours whereas fecal excretion is
high and, as shown by Stanbury and Lumb may exceed the dietary intake. This altera-
tion reflects the marked diminution in absorption of calcium from the gastrointestinal
tract, attributed in part to the postulated suppression of the conversion of vitamin D to its
active metabolite and in part to a direct suppression of calcium transport across the gut
wall caused by the hyperphosphatemic uremia 18.196.273.348,349#{149} The serum calcium levels in
patients with uremia are somewhat variable The values reported
65.191.198.348, are generally
low, but marked hypocalcemia (below 7.5 milligrams per 100 milliliters) is unusual, and
normal values are occasionally encountered. Since the uremic patient is acidotic and often
hypoalbuminemic, the percentage of the total serum calcium in the ionized form is often
considerably higher than normal 65.155.167; hence, patients with very low values for total
calcium may not have tetany or hypertonia.
Parathyroid function and parathormone excretion are also affected, despite the in-
crease in the ionized fraction of the serum calcium. In most uremic patients there is
sufficient hypocalcemia to cause a feedback stimulus to the parathyroid glands to release
parathormone 2.4.273.35() Berson and Yalow 30 have shown significant increases in
parathyroid hormone in patients with chronic uremia, and at autopsy most patients dying
of renal failure have diffuse clear-cell hyperplasia of the parathyroid glands 52.140.186 (see
Figs. 8.A, 8-B, and 8-C, Part I).
The concentration of the serum inorganic phosphate in the early stages of uremia is
low, but as functional impairment of the kidneys increases the concentration begins to
rise 143.144.245.27:3 Hyperphosphatemia usually becomes manifest when renal function is
reduced to 20 to 30 per cent of normal 144#{149} The increased serum phosphate levels are pre-
sumed to be caused by a decrease in glomerular filtration of phosphate rather than an alter-
ation in tubular reabsorption 65.144.245.273.335#{149} Several studies of tubular function in patients
with chronic renal disease have shown that the rate of reabsorption is abnormally

low , presumably because of the increased levels of parathyroid hormone.

As a result of these metabolic aberrations, the uremic acidotic patient has hypocal-
cemia, hypocalciuria, and hyperphosphatemia, as well as excessive excretion of calcium
in the colon and diminished absorption of calcium from the gut 245.273.348#{149} The osseous
lesions created by these changes are a combination of rickets or osteomalacia and classic
osteitis fibrosa cystica 186,273#{149} It is likely that the acidosis and other abnormalities accom-
panying the uremic state also decrease the rate of bone formation and increase the rate of
absorption of calcium from trabecular and cortical bone, possibly by favoring the forma-
tion of a labile calcium carbonate bone salt at the expense of the more stable calcium
apatite 167.211,273.281.341
The pathogenesis of the other skeletal abnormalities seen in renal osteodystrophy is

more obscure. The cause of osteosclerosis, which occurs in about 20 per cent of the pa-
tients with chronic renal disease, is unknown 74.147.193.205,362,369 It has been suggested that
it represents an exaggerated response of bone during a ‘ ‘healing phase’ ‘ when excessive
amounts of osteoid are laid down and rapidly mineralized. A second theory is that there is
a factor in the hormone elaborated by the parathyroid gland which acts to increase bone
formation rather than diminish it, and that this factor becomes abnormally active in
uremic osteodystrophy, and occasionally in cases of osteomalacia or hyperparathyroidism
in which focal areas of osteosclerosis are noted 113 It has also been suggested that the
osteosclerotic lesions are the result of sporadic periods of excessive treatment with cal-
cium, vitamin D, or both, and that resorption which normally would ‘erase’ each of ‘ ‘
these “tree rings” is so impaired that the “rings” remain 75,113.162.193.245.273.381#{149}
Soft-tissue calcifications in patients with uremia are relatively frequent, particularly

since kidney transplantation and dialysis have prolonged the survival of patients with
renal disease. Calcifications may occur in arteries 8.137.235.271.303 cornea and
conjunctiva 1.28,29,66,121,271 periarticular soft tissues 138.271,287,291 and the thoracic and ab-
dominal viscera 254.271 Metastatic calcification is usually considered to be a consequence
of an increased concentration of calcium or phosphate, or both, in the serum, to such a
degree that the solubility product of CaHPO4 is exceeded 245,271,273#{149} Circumstances which
would favor this state include an acute reduction in the degree of acidosis; an increase in
the serum calcium, such as the increase associated with the disuse osteoporosis resulting
from forced bed rest; or a sudden rise in serum phosphate, such as the rise that accom-
panies worsening of the disease. Treatment may also influence the genesis of the syn-
drome, since sudden reversals of the acidosis or increases in the serum calcium level may
occur during dialysis or with increments in the amount of calcium or vitamin D
administered 48,59,62.275 Serum phosphate may also rise as the result of exogenous dietary
increases.
The clinical manifestations of renal osteodystrophy vary considerably, depending on
the severity of the kidney disease and the degree of the associated calcium, phosphate,
vitamin D, and parathormone abnormality. In children, there is often severe impairment
of growth which roughly parallels the severity of the disease. Unless the child is very ill,
the classic signs of rickets are usually present. Since the onset of renal disease is relatively
late, craniotabes and frontal bossing are less frequent than a rachitic rosary or Harrison’s
groove 127.186.273, and bowing and other deformities of the extremities are common. En-
largement ofthe wrists and ankles may be the presenting complaint 186,273,347.348
Unlike patients with renal tubular or deficiency rickets, patients with renal osteodys-
trophy are remarkably prone to epiphyseal separation and metaphyseal fractures, and there
have been a number of reports of slipped capital femoral and humeral epiphyses occurring
in patients with chronic renal disease 37,53,77.197,324#{149}
The manifestations of secondary hyperparathyroidism are more subtle than those as-
sociated with rickets, and often it is only a pathological fracture or skeletal deformity that
leads to the diagnosis. The usual complaints and physical findings of patients with classic

368 H. J. MANKIN
FIG. 1-A FIG. 1-B

Figs. 1-A, 1-B, and 1-C: Osteoscierosis and soft-tissue calcification in renal osteodystrophy.
Fig. 1-A: Occasionally roentgenograms of a patient with renal osteodystrophy show areas of increased bone
density. (Reprinted by permission from Cyclopedia ofMedicine, Surgery, Specialties. Philadelphia, F. A. Davis
Co.. 1973.)
Fig. 1-B: Histologically there are increased numbers of trabeculae, but osteoid seams and other changes of
renal osteodystrophy are still present ( x 100).
hyperparathyroidism are often masked by the underlying renal disease, and since true
hypercalcemia rarely occurs the physiological changes caused by this alteration are usu-
ally not evident 273.347.348 The osteosclerosis is totally asymptomatic.
Soft-tissue calcification in chronic renal osteodystrophy may be identified readily by
palpation of arteries 235:303 or by examination of the skin 254.287.291, cornea, and
conjunctiva 1.28.29,66 Calcifications of the periarticular soft tissues may be palpable as
hard masses in the soft tissue, or there may be significant deformity or disability in joint
function, depending on the location and size ofthe metastatic calcific deposits 138,271
The roentgenographic changes in renal osteodystrophy are often quite

striking 74.94.147.369 In addition to the changes of rickets or osteomalacia, there is fre-
quently evidence of fairly marked osteitis fibrosa cystica. Dental roentgenograms may
show loss of the lamina dura, and sometimes cystic lesions in the mandible Diffuse
rarefaction of the bones is usually present, and is often subperiosteal
there resorption of
the cortices, particularly in the small bones of the hands and feet. ‘Cystic’ ‘ ‘ areas corre-
sponding to ‘ ‘brown tumors’ ‘ may be evident in the shafts of the long bones or in the flat
bones 147,186 (see Fig. 8-C, Part I). Favorite sites for irregular resorptive lesions are the
outer ends of the clavicles, the cortices of the proximal phalanges and metacarpals, and
the medial side of the proximal portion of the tibia 94.147.186 Compression fractures of the
vertebrae are also common I,
Areas of osteosclerosis may also be present. They usually appear as localized in-
creases in density of the trabecular pattern or as a diffuse chalky density which obscures
the normal bone architecture 147.186.205,362,381 (Figs. 1-A and 1-B). When osteosclerosis
occurs in the spine it may produce sclerosis of the superior and inferior vertebral borders,
the so-called rugger-jersey spine of Dent and Hodson Other common sites are the pel-
vis, ribs, and femora, and occasionally the facial bones 94,147,186
Soft-tissue calcification may appear rapidly in patients with renal osteodystrophy,
particularly those under treatment with dialysis. Vascular calcifications usually occur in

RICKETS, OSTEOMA LACIA, AND RENAL OSTEODYSTROPH Y 369
FIG. 1-C
Arterial calcification seen in a patient with chronic renal failure.
the small vessels

of the hands and feet, but may involve most of the arterial trunks 137
(Fig. 1-C). patterns have been described:
Two small, discrete, dense shadows represent-
ing calcification ofatheromatous plaques; and less dense, diffuse, pipe-stem shadows rep-
resenting calcification ofthe media 147,271 Soft-tissue calcification about thejoints may be
in tendon and ligament insertions, menisci, and articular cartilages 140,147 Common sites
are the menisci of the knee and the triangular ligaments of the distal radio-ulnar
joint 45,140,271The deposits in the knee may resemble those seen in pseudogout and may at
times produce acute arthritic symptoms consistent with that diagnosis 45,227,
Renal osteodystrophy may be diagnosed readily by the laboratory findings 245,273,348
In addition to the findings of chronic renal disease, the serum calcium is usually low or
low normal, the phosphate is invariably elevated, and the alkaline phosphatase is usually
above normal. Urinary excretion of calcium is almost always markedly diminished and
fecal excretion is increased.
The treatment ofrenal osteodystrophy is difficult, chiefly because complications may
arise when attempts are made to alter the serum levels ofcalcium and phosphate 1)6,117,286
High doses of vitamin D are sometimes effective in increasing absorption of calcium 192
and an increased dietary intake ofcalcium is usually indicated, but must be instituted with
caution 273 Such treatment is sometimes effective in reducing the manifestations of both
rickets and secondary hyperparathyroidism. Oral administration of aluminum hydroxide
may reduce the serum phosphate and decrease the bone abnormalities 286, Dialysis is
clearly of value in reducing the urea content of the blood and acidosis, and proper compo-
sition ofthe dialysis fluid can also correct the calcium and phosphate abnormalities 275.304
The risk of acute hypocalcemia, soft-tissue calcification, or dialysis osteopenia must be

kept in mind during such therapy, and every effort must be made to maintain the serum
concentrations of calcium and phosphate within the narrow normal range and below the
solubility product 0fCaHPO4 I,48,273.275,304#{149} Several recent reports suggest that the lesions
of renal osteodystrophy may be completely cured by successful renal
transplantation 7,77,154,378
An occasional patient with uremic osteodystrophy may have extraordinarily severe

secondary hyperparathyroidism which does not respond to reversal of the metabolic de-
VOL. 56-A, NO. 2. MARCH 1974

370 H. J. MANKIN
fects by medication, dialysis, or even renal transplantation. In such cases the parathyroid
glands are believed to be “autonomous,” and it has been suggested that the hyperplasia
has become an adenoma 112.273.282.363, the condition sometimes being referred to as tertiary
hyperparathyroidism 50.l00,232#{149} Subtotal or complete resection of the hyperplastic or
‘ ‘adenomatous’ ‘ parathyroid glands may be necessary to control the patient’s abnormal
metabolic state 77.112.117.171,345.351
Unusual Forms of Rickets and Osteomalacia

Rickets and Osteomalacia Associated with Fibrous Dysplasia
In 1961 , Halvorsen and Aas 152 described a patient who had typical hypophos-
phatemic vitamin D-resistant rickets in association with florid polyostotic fibrous dys-
plasia. Kunin 203 in 1962 and Ryan and associates 306 in 1968 described two more pa-
tients with virtually identical findings. Although coincidental occurrence ofthese two rare
syndromes could have occurred, the uniformity of the clinical picture presented by all
three patients suggests some association. Since polyostotic fibrous dysplasia may be as-
sociated with significant hormonal abnormalities, including precocious puberty in females
and thyrotoxicosis , it is reasonable to suggest that vitamin D-resistant rickets should be
added to this list of associated abnormalities.
Rickets and Osteomalacia Associated with Neurofibromatosis

In 1954, Swann reported on four patients in whom rickets and osteomalacia were
associated with neurofibromatosis (von Recklinghausen’ s disease). From the descriptions
of these patients and others ‘ ‘ , it is apparent that most of them had a high resistance to
vitamin D. A personally treated patient showed classic findings of vitamin D-resistant
rickets and required over 100,000 units of vitamin D per day to elevate the serum phos-
phate to above 2.5 milligrams per milliliter 236 (see Fig. 6-D, Part I).
For those intrigued by eponyms, it is perhaps worth noting that in neurofibromatosis
with rickets the two diseases originally described by von Recklinghausen 181.186
(neurofibromatosis and osteitis fibrosa cystica generalisata caused by hyper-

parathyroidism) can occur in the same patient. To confuse the issue further, polyostotic
fibrous dysplasia, which has certain features in common with neurofibromatosis (caft au
lait spots, pseudarthrosis of the tibia, and some of the histological changes), in the older
literature was sometimes called osteitis fibrosa cystica disseminata 5.186#{149} Patients with
rickets associated with polyostotic fibrous dysplasia may therefore have coincident osteitis
fibrosa cystica generalisata and osteitis fibrosa cystica disseminata.
Rickets and Osteomalacia Associated with Benign Bone and Soft-Tissue Tumors
A number of adult patients have now been described who had hyposphatemic vitamin
D-resistant osteomalacia, apparently secondary to certain benign tumors of the skeleton
or soft parts. The “primary” neoplasms included hemangioma of bone 308, giant-cell
tumor 51 reparative giant-cell granuloma 289, non-ossifying fibroma of bone 288, cavern-
ous hemangioma ofthe thigh 92, and “ossifying mesenchymal tumor” of the larynx 266#{149}
In all of these patients resection of the neoplastic lesion was followed by prompt disap-
pearance of the metabolic abnormality, although one had ‘ ‘tertiary hyperparathyroidism”
after removal of the tumor 266 Salassa and co-workers 308 suggested that these tumors
were producing ectopic humoral substances (possibly vitamin-D antagonists 266) which
caused hypophosphatemic osteomalacia unresponsive even to massive doses of vitamin
D.
Rickets and Osteomalacia Associated with Anticonvulsant Therapy
In 1968, Kruse 202 reported that 15 per cent of epileptic patients on long-term treat-
ment with anticonvulsant medication showed chemical and roentgenographic evidence of

osteomalacia. The extent of these changes appeared to be related to the dose and duration
of drug therapy. Since this report 202, there have been a number of others on patients re-
ceiving maintenance therapy with diphenylhydantoin, phenobarbital, and other anticon-
vulsant medications, in whom classic rachitic or osteomalacic diatheses
developed 12.35.58.97.l28.l39.l74,206.299 The disorders of calcium and phosphate metabolism
occur in 15 to 30 per cent ofthe patients on medication; but generally they are described as
being mild and appear to respond well to moderate doses of vitamin D.
The pathogenesis of these skeletal changes has not been completely elucidated, but
the experimental studies of Dent and associates ‘ suggest that vitamin D is inactivated
more rapidly in patients who are under treatment with the hydantoin family of drugs, and
Hahn and co-workers 148 have shown that the plasma levels of 25-hydroxy vitamin D are
reduced in patients receiving phenobarbital for long periods of time. The mechanism re-
sponsible for this effect appears to be related to the stimulation of hepatic microsomal
P-450 enzymatic activity, with resultant accelerated degradation of vitamin D3 and
25-hydroxy vitamin D to inactive metabolites
The rachitic and osteomalacic disease seen in these patients is relatively mild and
usually responds well to vitamin D. It is, nonetheless, an important syndrome, since the
hypocalcemia which may develop as a result of anticonvulsant medication can lead to
tetany, hypertonus, and central nervous system irritability, thereby increasing the mci-
dence of seizures. More frequent or more severe seizures on this basis may cause the
physician to increase the anticonvulsant medication, and thereby start an iatrogenic cycle
which may produce significant osseous and central nervous system lesions 97,299#{149} Patients
on anticonvulsant medication should have periodic evaluations of their serum calcium,

phosphate and alkaline phosphatase, and should be treated with vitamin D if an abnormal-
ity is noted.
Hypophosphatasia
Hypophosphatasia resembles rickets clinically , roentgenographically , and to some
extent histologically, but it is a separate entity and by some definitions of rickets should
not be classified with this group of diseases. The disorder appears to result from a genetic
error in synthesis of alkaline phosphatase and is transmitted as an autosomal recessive.
Asymptomatic heterozygotes may be readily identified by determination of their serum
alkaline phosphatase 226 and analysis of their urine for the presence of excessive amounts
of phosphoethanolamine 145,226
Hypophosphatasia was named by Rathbun 294 in 1948, but the disease was described
as early as 1929, when it was considered to be a variant ofrickets 25,172 A decreased level
of serum alkaline phosphatase was first noted in a patient described by Anspach and
Clifton 10 in 1939. Studies by Rathbun 294 and later by Sobel and associates demon-
strated a widespread decrease in concentration of alkaline phosphatase in bone, cartilage,
liver, intestinal mucosa, and kidney. In 1955, McCance and associates 225 and also Fraser
and co-workers 134 described increased concentrations of phosphoethanolamine in the
serum and urine of asymptomatic heterozygotes.
Affected patients usually show changes early in life 131.226.294#{149} The principal symp-
toms and signs are growth retardation, failure to thrive, irritability, fever, vomiting, con-
stipation, and signs of increased intracranial pressure. The cranium is poorly ossified, and
frequently there is craniosynostosis 226 The suture lines may be enlarged and resemble
craniotabies. Dentition is often delayed, and the teeth may show extensive caries 284#{149} The
peripheral epiphyses are often enlarged and the costochondral junctions are prominent.
Genu valgum or varum may develop. In recent years, a less severe adolescent form and an
even milder adult variant have been described 25.31
Roentgenograms may show generalized rarefaction of the skeleton, most marked in

the calvarium and metaphyseal areas 78 The long bones are frequently bowed, and in the

372 H. J. MANKIN
regions of the epiphyseal plates there are peculiar cup or wedge-shaped deformities of the
metaphyseal components, with irregular notches at the margins 46.78#{149} The epiphyseal cen-
ters of ossification and round bones are regular in outline but otherwise unaffected except
for the generalized rarefaction 46#{149}
Histological examination shows large quantities of unmineralized osteoid in the

bones, particularly in areas of active growth and in the region of the synostotic cranial
sutures 226 The epiphyseal cartilages are irregular, with lengthening of the columns and
decreased vascular invasion and mineralization 25,186,294
It is postulated that this genetic disease is caused by an unknown enzymatic abnor-

mality which diminishes the amount of alkaline phosphatase 201.226 and pyrophosphate in
the tissues 305 The exact mechanism ofthis defect is unknown, and its effect on the skele-
ton is not well understood 25.201 Patients with hypophosphatasia uniformly have very low
levels of serum alkaline phosphatase 25.134.294.343, while their serum calcium and inorganic
phosphate are usually normal. An occasional patient is moderately hypercalcemic, a
finding as yet unexplained. There is no evidence for parathyroid hyperfunction, but some
data have suggested the possibility that this disorder may be associated with a hypersen-
sitivity to vitamin D 25 An unusual feature ofthe disease is the increased serum concentra-
tion and excessive urinary excretion of phosphoethanolamine 134.145.225.294#{149} The
significance ofthis finding is at present unknown.
Infants with hypophosphatasia may have serious systemic difficulties, with increased
intracranial pressure, hypercalcemia, renal failure, or overwhelming infection. Despite
supportive measures, the mortality rate is high, ranging from 50 to 70 per cent 78.127#{149}
Juvenile and adult patients with the disorder are less severely affected, but may have
marked skeletal deformities and dwarfism. A recent report suggests that in patients with
this disorder osteotomies (and possibly fractures) heal very slowly, and that prolonged
immobilization may be required 184#{149}
The Treatment of Rickets and Osteomalacia
Treatment of the various forms of rickets and osteomalacia varies widely depending
on the etiology of the disease and the severity of its manifestations and metabolic abnor-
malities. There is no simple regimen or even group of therapeutic routines for such a var-
iegated group of entities, and even within each category the treatment must be carefully
tailored to the needs of the individual patient. In general, treatment involves the adminis-
tration, in appropriate amounts and combinations, of vitamin D, calcium, phosphate, and
alkalinizing solutions. Orthopaedic measures may be required to correct deformities that
cannot be expected to improve with growth.
Vitamin D
Crystalline vitamin D is the major therapeutic agent in most forms of rickets. It is
apparently of little consequence whether D2 or D3 is administered, and the units of meas-
urement are the same for both. The dosages were previously expressed in terms of biologi-
cal activity according to an international unit system 245.261 , with an estimated average
daily requirement ranging from 200 to 400 I. U. per day for children and from 100 to 400
I. U. per day for adults 245,261.274#{149} The requirement is increased during pregnancy and
lactation 185,261 Recently, because the vitamin is obtainable in pure form, there has been a
tendency to express dosage in terms of weight: one milligram of crystalline vitamin D2 or
D3 i5 equivalent to 40,000 I. U. , or, conversely, one I. U. equals 0.025 micrograms of
vitamin D 272.274
The dose and route of administration of vitamin D required for the treatment of rick-
ets varies widely depending on the type of rachitic syndrome, the age of the patient, the
severity of the process, and the anticipated difficulty in absorption of the fat-soluble
sterol 18.127.133,245,274 In patients with uncomplicated vitamin D-deficient rickets, it is

theoretically possible that ten micrograms (400 I.U.) per day would be sufficient to cure
the disease, but most authorities advise doses ranging from ten to 100 times this amount
(100 micrograms to 1 milligram; 4,000 to 40,000 I.U. per day). There is little danger of
vitamin-D toxicity at this dose range, and the material is well tolerated. For patients with
absorptive defects, the material can be administered intravenously or intramuscularly (at a
moderate reduction in dose and frequency of administration), but there is usually no need
for such a procedure, since even the most refractory of the gastrointestinal rachitic states
responds reasonably well to oral administration of pharmacological doses of vitamin-D
preparations. Under ordinary circumstances, in a patient with deficiency rickets or os-
teomalacia there is no need to supplement the vitamin-D therapy with calcium or phos-
phate, although one should be sure that the intake ofthese materials is adequate 274,337
In the treatment of the vitamin D-resistant rickets and osteomalacia, the recom-
mended dosage level of vitamin D varies widely. Older texts and articles suggested that
the range necessary for adequate treatment varied from 2.5 to 25 milligrams per day or
more (100,000 to 1 ,000,000 I.U. per day or more) 127,245.265.274 More recent studies have
indicated that these high dose schedules not only are not effective in controlling the dis-
ease but may in fact worsen it 271.357, and that there is a high risk of complications of
hypervitaminosis-D, hypercalcemia, and nephrocalcinosis 283,346,352 The toxic state as-
sociated with massive doses of vitamin D is often subtle 9.56,178, and there may be acute
crises precipitated by such events as prolonged bed rest or immobilization associated with
surgical treatment 283.346#{149}Stearns, in 1964 352, described a technique of administration of
vitamin D to patients with vitamin D-resistant rickets based on daily calcium intake, body
weight, and the urinary calcium excretion per twenty-four hours. However, even with
such safeguards problems may arise and the patients often show serious toxic effects.
Two other vitamin-D preparations should be mentioned. Dihydrotachysterol (A .T.
10) is a synthetic sterol with antirachitogenic properties. The material is of little value in
vitamin D-deficient states ‘, but may be efficacious and reasonably safe in patients with
vitamin D-resistant rickets or hypoparathyroidism 159.163.188.245.271,274.310,373 The dosage
recommended is about one third that of vitamin D, ranging from 0.3 to 0.75 milligrams
daily 271#{149}Several families with vitamin D-resistant rickets have been treated with low to
moderate doses of 25-hydroxy vitamin D by Pak and associates 270 and by Earp and
co-workers 104 The results to date are moderately disappointing 18,23, suggesting that the
pathogenesis in some cases of vitamin D-resistant rickets may not be associated with a
failure of production of either the 25-hydroxy or the 1 ,25-dihydroxy vitamin D’s. How-
ever, the polar metabolites have been found to be effective in the treatment of renal
osteodystrophy and hypoparathyroidism 269
Calcium
For patients with osteomalacic syndromes and hypocalcemia, administration of cal-

cium has the obvious advantage ofdirectly correcting the metabolic deficit and the impor-
tant secondary effect of diminishing the feedback stimulus to the parathyroid glands, thus
reducing the renal phosphate leak and bone resorption 127.204#{149} Orally administered calcium
requires vitamin D for absorption from the gastrointestinal tract, and the amount which
can be easily administered is limited. Calcium salts complex to phosphate, fatty acids, and
other materials, and may produce fecoliths or decrease intestinal motility if given in large
quantities. The usual amount of calcium that can be taken by mouth is 1 to 1 .5 grams per
day. If sufficient vitamin D is administered up to 0.5 gram may be absorbed, but the pos-
sibilities of hypercalcemia and metastatic calcification exist, particularly if the treatment is
prolonged in older individuals or in patients with poor renal function or hyperphos-
phatemia. Calcium infusions do not require vitamin D for absorption but are hazardous
because of the possibility that a transient hypercalcemia can result in nephrocalcinosis,
vascular calcification, or cardiac arrhythmias. There is probably no place for the use of

374 H. J. MANKIN
intravenous calcium in the treatment of the rachitic syndromes except in an emergency

such as acute hypocalcemic tetany or impending cardiac failure.
Phosphate
Oral administration of phosphate solutions in combination with large doses of vita-
mm D has been shown to be effective in the treatment of vitamin D-resistant rickets with
or without acidosis The solutions
82,130.242.274,30I.370,375 suggested by several investigators
contain between one and six grams ofelemental phosphorus. No serious side effects from
use of these solutions have been reported 82.127.242.274.370#{149} The administration of a phos-
phate solution should in most cases be accompanied by adequate vitamin-D therapy. With
such combined therapy the dosage of the sterol frequently can be reduced markedly, thus
decreasing the hazards of vitamin-D toxicity. Of some concern when high doses of phos-
phate are given is the possibility that the severity of the secondary hyperparathyroidism
may be increased 274
Phosphate may also be administered by infusion, as reported by Steendijk and

others 106, but administration by this route must be very carefully monitored because of
the possibility of nephrocalcinosis and metastatic calcification of the soft tissues 38
Alkalinizing Solutions
In patients with renal tubular acidosis, the metabolic defect may be almost entirely
corrected by alkalinization with a suitable oral (or, if necessary, parenterally adminis-
tered) supplement to the diet. There are numerous materials recommended. Sodium bicar-
bonate in a dosage often grams (120 milliequivalents) is usually effective 127,298 although
perhaps not as palatable as Shohl’s solution 328, which not only compensates for the
acidosis but adds potassium (0.9 milliequivalents per milliliter) which may be important
in patients with hypokalemia.
Alkalinizing solutions should also be administered to patients with proximal and dis-
tal Fanconi, Lignac-Fanconi, oculo-cerebral-renal, and superglycine syndromes, in com-
bination with neutral phosphate, vitamin D, and calcium I27.133.274,337#{149}
The treatment regimens for the various forms of rachitic and osteomalacic syndromes
recommended by different authorities vary considerably. The interested reader is referred
to reviews by Fourman and Royer 127, Fraser and Salter ‘, Smith and Parfitt and
Frame 274 for comprehensive surveys of the subject. Table IV provides an outline of the
most generally accepted ranges of dosage of vitamin D and the other agents used for the
various disorders. It is important to recognize the need for individualization of treatment
and for careful monitoring of therapy, not only to assess its effect on the chemical and
clinical manifestations of the disease, but also to prevent potentially life-threatening side
effects.
Monitoring treatment is complex and there is no single test which assesses the effect
of the treatment on all manifestations of the disease or provides warning of the hazards of
overdosage with vitamin D . Evaluation of the effect of treatment on the bone and cartilage
changes of the disease is best accomplished by serial measurements of the serum alkaline
phosphatase, which reflects the amount of new-bone formation, and by serial roentgeno-
grams of the wrists or knees, which should show progressive healing. Evaluation of the
treatment of the biochemical changes of the disorder is best assayed by serial measure-
ments of the serum inorganic phosphate. When the alkaline phosphatase and serum inor-
ganic phosphate return to the normal range and roentgenograms show progressive healing
of the disease, one may consider the treatment regimen adequate. If, in addition, there are
no side effects and the growth rate in children is reasonably maintained, the treatment can
be considered optimum. Occasionally, in adults with osteomalacia, repeated biopsies of
the iliac crest are necessary to demonstrate improvement in skeletal mineralization. Serial
determinations of the percentage of tubular reabsorption of phosphate may also help to
define any improvement in the handling of phosphate in the kidney.
TABLE IV
TREATMENT OF RICKETS AND OSTEOMALACIA
Suggest ed Treatment
Type of Neutral
Rickets or Osteomalacia Vitamin D Calcium Phosphate Additional Treatment
Vitamin D-deficient states 25-250 gig/day 1 g/day General nutrition; sunlight?

(1,000-10,000 I.U./day)
Absorptive defects 37.5-625 pg/day 1-2 g/day Treatment of underlying
(1,500-25,000 I.U./day) enteric pathology; where
appropriate, low-fat or
gluten-free diet
Vitamin D-resistant 0.5-1.5 mg/day* 1 g/day 1.5-6 g/day
rickets (20,000-60,000 I.U./day) (or less)
or dihydrotachysterol,
0.25-1 mg/day
Proximal Fanconi 0.6-1 mg/day 1 g/day 1-3 g/day
syndrome (25,000-40,000 I.U./day)
Proximal and distal 0.5-1 mg/day 1 g/day 1-3 g/day Alkalinizing solutions;
Fanconi syndrome, sufficient fluids to
Lignac-Fanconi overcome nephrogenic
syndrome diabetes insipidus; K
supplements
Renal tubular acidosis 25-100 pg/thy Alkalinizing solutions;
(1,000-4,000 I.U./day) K supplements
Renal osteodystrophy 0.5-5 mg/day 1-3 g/day Dialysis; homotransplanta-
(20,000-200,000 I.U./day) tion; parathyroidectomy;
or dihydrotachysterol, oral aluminum salts as
0.25-0.5 mg/day indicated
* This dosage requires simultaneous use of neutral phosphate. If phosphate is not used, considerably larger
doses of vitamin D are advocated.
Just as important as measuring the effect of treatment of the rachitic process, how-
ever, is the prompt recognition of potentially dangerous side effects resulting from over-
dosage with vitamin D or phosphate. This hazard can best be avoided by serial measure-
ments of the serum calcium and urinary calcium excretion. If the serum calcium rises to
above 1 1 milligrams per 100 milliliters or the urinary excretion of calcium exceeds 350
milligrams in twenty-four hours (in the adult), nephrocalcinosis or soft-tissue calcification
may occur, particularly in patients whose phosphate levels have returned to normal or are
high on the basis ofrenal glomerular disease.
The management of patients with renal tubular acidosis and renal osteodystrophy is
very complex, and the rachitic or osteomalacic disease cannot be separated from the prob-
lems associated with acid-base balance and mineral metabolism. In the treatment of
chronic renal failure , dialysis , homotransplantation , and associated immunosuppression
add additional complexities to the problems of care. The interested reader is referred to
several recent review articles and symposia 151,156,I98.245.265.275
Orthopaedic Measures
Patients with rickets, osteomalacia, or renal osteodystrophy frequently are seen by

orthopaedists with complaints ofgrowth disturbance, limb deformity, weakness, and mul-
tiple fractures. In addition to the systemic treatment just described, certain orthopaedic
measures are of value in correcting long-standing deformities and disability associated
with the disease 36.280.283.346,361
In infants with deficiency rickets, if effective treatment is given sufficiently early the
skeletal deformities usually correct spontaneously and there is little need for orthopaedic
treatment other than careful observation. In long-standing cases of deficiency disease and
of vitamin D-resistant rickets, orthopaedic management may be of value. Properly de-
VOL. 56-A, NO. 2, MARCH 1974

376 H. J. MANKIN
signed braces for the extremities may, over a period of years, correct milder degrees of
bowing or knock-knee deformities, but surgical procedures such as osteotomy ofthe tibia
or femur may be necessary for long-standing, marked deformities. There is generally little
problem with bone healing and union occurs fairly rapidly, except perhaps in patients with
hypophosphatasia Patients
184#{149} with vitamin D-resistant states who are maintained on high
doses of the sterol should have their dose reduced whenever bed rest is required, in order
to minimize calcium mobilization and help to prevent the nephrocalcinosis which may
occur as a result of disuse osteoporosis 243,280,283.346,361
Surgical management of the bone lesions of patients with renal osteodystrophy is

considerably more complicated, chiefly because of the severity of the metabolic abnor-
malities. In 1966, Shea and Mankin 324 expressed the view that patients who have renal
failure complicated by a slipped capital femoral epiphysis should be treated conservatively
because of the severity of their illness and their limited life span. Numerous advances in
the care of the azotemic patient have been made since this erroneous concept was ad-
vanced, and there is now ample evidence that such patients, or those who have osteone-
crosis secondary to immunosuppression after renal homotransplantation, can be improved
considerably by appropriate surgical procedures 53.77.151.156
Summary
Rickets and osteomalacia may result from a wide spectrum of inherited and acquired
metabolic abnormalities which produce sufficient decrease in serum calcium, phosphate,
or both to impair mineralization of the skeleton and epiphyseal growth. Although these
various abnormalities may cause strikingly similar findings in affected patients, the re-
spective diseases can usually be separated and identified by careful evaluation ofthe clini-
cal, roentgenographic, and laboratory data. The prognosis and treatment may vary con-
siderably depending on the cause of the rickets or osteomalacia. Each patient must be
carefully studied and treated with the appropriate regimen for his or her particular
metabolic abnormality.
NOTE: The author wishes to acknowledge the contributions of Dr. Henry Jaffe, Dr. Howard Dorfman. and Dr. Alex Norman, who generously
supplied some ofthe illustrations.
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9 Rickets, Osteomalacia, Renal Osteodystrophy - Jbjs Part 2

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Review Article

Rickets, Osteomalacia, and

BY HENRY J. MANKIN, M.D.t, BOSTON, MASSACHUSETTS

Etiological Classification and Diagnosis of Rickets and Osteomalacia

As already indicated, the syndromes of rickets (and osteomalacia) are pathogeneti-

Inadequate intake of calcium or phosphorus, or insufficient vitamin D in the diet, in

352 THE JOURNAL OF BONE AND JOINT SURGERY

I. Deficiency Rickets and Osteomalacia

VOL. 56-A, NO. 2, MARCH 1974

scleroderma, amyloidosis, regional enteritis, and tuberculous enteritis 245,264.386#{149} In addi-

Rickets and Osteomalacia Due to Renal Tubular Abnormalities

THE JOURNAL OF BONE AND JOINT SURGERY

enzyme systems in the renal tubule. These mechanisms produce a hypophosphatemic

Proximal Tubular Rachitic and Osteomalacic Syndromes

vitamin D 15.18.373 According to this concept, vitamin D, when present in physio-

VOL. 56-A, NO.2, MARCH 1974

Renal R eabsorp tive Defect

Proximal tubular syndromes

vitamin D-resistant rickets, otherwise known as hypophosphatemic rickets or phosphate

Roentgenographic studies demonstrate typical alterations in the epiphyseal lines, in-

THE JOURNAL OF BONE AND JOINT SURGERY

produced a striking remission in the disease, and subsequent administration of parathor-

Proximal and Distal Renal Tubular Rachitic and Osteomalacic Syndromes

In addition to the hypophosphatemic diathesis, however, these patients have other

VOL. 56-A, NO.2, MARCH 1974

The Lignac-Fanconi syndrome is now fairly clearly identified as a genetic disease

THE JOURNAL OF BONE AND JOINT SURGERY

VOL. 56-A, NO. 2, MARCH 1974

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Although the oculo-cerebral-renal syndrome is listed with the vitamin D-resistant

4. The superglycine syndrome, otherwise known as hypophosphatemic rickets with

Rickets and Osteomalacia Associated with Renal Tubular Acidosis

Renal tubular acidosis is a clinical syndrome caused by disordered acidification of the

Frequently water reabsorption is also decreased, resulting in profound dehydration. The

VOL. 56-A, NO.2, MARCH 1974

parathyroidism, phosphaturia, hypophosphatemia, and bone lesions. The effect of

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pyelonephritis 207, or drug sensitivity or intoxication 94,109,230 Although the handling of

Chronic glomerular renal

VOL. 56-A, NO.2, MARCH 1974

Calcium metabolism has also been studied extensively in uremic

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low , presumably because of the increased levels of parathyroid hormone.

The pathogenesis of the other skeletal abnormalities seen in renal osteodystrophy is

these “tree rings” is so impaired that the “rings” remain 75,113.162.193.245.273.381#{149}

Soft-tissue calcifications in patients with uremia are relatively frequent, particularly

VOL. 56-A, NO.2, MARCH 1974

FIG. 1-A FIG. 1-B

The roentgenographic changes in renal osteodystrophy are often quite

THE JOURNAL OF BONE AND JOINT SURGERY

the small vessels

Renal osteodystrophy may be diagnosed readily by the laboratory findings 245,273,348

The risk of acute hypocalcemia, soft-tissue calcification, or dialysis osteopenia must be

An occasional patient with uremic osteodystrophy may have extraordinarily severe

VOL. 56-A, NO. 2. MARCH 1974

Unusual Forms of Rickets and Osteomalacia

Rickets and Osteomalacia Associated with Neurofibromatosis

(neurofibromatosis and osteitis fibrosa cystica generalisata caused by hyper-